Inspections, Compliance, Enforcement, and Criminal Investigations
Cincinnati Sub-Zero Products Inc 7/13/10
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Cincinnati District Office|
6751 Steger Drive
Cincinnati, OH 45237-30977
Telephone: (513) 679-2700
FAX: (513) 679-2761
July 13, 2010
Via United Parcel Service
Mr. Steven J. Berke
President and CEO
Cincinnati Sub-Zero Products, Inc.
12011 Mosteller Road
Cincinnati, Ohio 45241
Dear Mr. Berke:
During an inspection of your firm located in Cincinnati, Ohio on October 15, 2009 through December 14, 2009, investigator(s) from the United States Food and Drug Administration (FDA) determined that your firm manufactures the Blanketrol II, Blanketrol III, Electri-Cool II, Micro-Temp LT, Hemotherm, Norm-O-Temp, Extra Corporeal Membrane Oxygenation Blood Temperature Control System, and Warm Air Hyperthermia System Model 135. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body.
This inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Act (21 U.S.C. § 351(h)), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. We received responses from you dated January 27, 2010, February 26, 2010, and April 9, 2010 concerning our investigator's observations noted on the Form FDA 483, List of Inspectional Observations that was issued to you. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
1. Failure to establish and maintain adequate procedures for implementing corrective and preventive actions, as required by 21 CFR 820.100(a). According to your document SOP 8.5.2/8.5.3(S), "Corrective & Preventive Action Procedure," Rev. 10, section 6.1.2, implemented 9/9/09, you are required to monitor "any product deviation confirmed to have taken place three (3) or more times per quarter of the same calendar year or six (6) or more times within the same calendar year" using the reasons listed in sections 6.1.1 to 6.1.8. For example:
a. You failed to investigate the cause of nonconformities relating to product, processes, and the quality system. Specifically, SOP 8.5.2/8.5.3(S), section 6.1.3 requires analysis of "Any deviation confirmed by the Quality Director, Quality Manager, Assistant Quality Manager, or his/her designee which determines the event(s) may cause user harm, considerable customer dissatisfaction, or significant cost" for CAPA initiation. Suspect breaches of sterile packaging and seal failures in approved product was documented in Complaint 08836 which was closed on 5/4/09 and Nonconforming Material Reports 0007096 and 0007097 which was opened on 9/29/09. No Corrective Action for debris in the seal of a sterile product was initiated. No investigation was performed on this or any other sterile product processed using the Bar Sealer pouch sealer. Subsequent investigation in your manufacturing area identified products being sealed in pouches with compromised or open seals as acceptable.
b. You failed to verify or validate the corrective and preventive action to ensure such action does not adversely affect the finished device. You received seven complaints for leaks at the reservoir elbow of Blanketrol II and III devices in a calendar year but did not open a CAPA according to SOP 8.5.2/8.5.3(S), section 6.1.2.
c. You failed to provide evidence to demonstrate field action completion for the closure of CAPA M2009-030, which required that a field action be performed for the cracking of heater plates in Micro-Temp LT devices.
We have reviewed your responses and have concluded that they are inadequate because:
a. You provided an action plan for the resolution of supplier evaluation of (b)(4) and improvements of the supplier evaluation and nonconforming material resolution, including the implementation of a CAPA. However, you have not determined the fundamental cause for a systemic failure to analyze complaints, returned product, and other quality data sources, and no corrective action or preventive action to correct the systemic failure has been taken and determined to be effective.
b. You stated that a corrective action had been opened following the inspection, wherein the device was found to be inadequate, a new device was ordered and validated for its intended use, and you returned to production with the new pouch sealer. Additionally, you performed a retrospective validation on all processes which require validation and are creating new visual standards for the operation of the pouch sealer. However, the effectiveness of the CAPA and specifically your preventive action has not been determined. The equipment and process validations mentioned have not been submitted for review. You have also not determined the fundamental cause for a systemic failure to evaluate nonconformances, and no corrective action or preventive action to correct the systemic failure has been taken and determined to be effective.
c. You opened a corrective action to re-evaluate the effectiveness of CAPA M2007-016 and reopened CAPA M2009-030 to re-evaluate the effectiveness. Additionally, you concluded that no field action was needed to address the cracking of heater plates in Micro-Temp LT devices. However, you have not concluded root causes and no corrective action or preventive action have been taken and been determined to be effective. You have also not determined the fundamental cause for a systemic failure to ensure that corrective and preventive actions will be validated or where appropriate verified, and no corrective action or preventive action to correct the systemic failure has been taken and determined to be effective.
2. Failure to establish and maintain adequate procedures to analyze appropriate sources of quality data to identify existing and potential causes of nonconforming product and other quality problems, as required by 21 CFR 820.100(a)(1). For example:
a. You received letters that included reports and data from a microprocessor board supplier documenting the nonconformance investigations of microprocessing boards returned to the supplier. Document SOP 8.5.2/8.5.3(S), "Corrective & Preventive Action Procedure," Rev. 10, section 6.1, implemented 9/9/09, states a "[CAPA] will be initiated to evaluate an occurrence or trend of a gross or uncommon failure within the scope of the following deviations;" section 6.1.8 identifies "supplier performance issues." However, no documented evidence of analysis of this data to determine if they were analyzed to open a CAPA was provided, and you admitted that supplier performance information was not analyzed. These reports represent a quality data source that you do not analyze.
b. You provided charts to investigators as evidence of complaint trending to demonstrate compliance with SOP 8.4(M), "Analysis of Quality Metrics." The provided "Board Complaint Pareto" chart showed 56 complaints for the Blanketrolline of products for microprocessor board complaints from 1/2007 to 10/2009. A subsequent chart titled "Board Complaints" showed no board complaints for September/October 2009. A review of your complaint files indicated that complaints were received for microprocessing boards in these months (complaints 10772, 10802, 10865,10874, 10929, 11020, 11043, 11038, and 11023). These complaints were not included in trending analyses.
c. You provided a chart to investigators titled "Complaints by Product Pareto," which showed 59 complaints related to microprocessing board issues with Electri-Cool devices. However, the raw complaint data for these 59 complaints were found to include microprocessing board complaints related to other devices than Electro-Cool devices and evidence that these were being analyzed was not proved.
We have reviewed your responses and have concluded that they are inadequate because:
a. You opened a CAPA to investigate the trend in microprocessor boards, and also created and sent the microprocessor board supplier a supplier evaluation form akin to an investigation. Document SOP 8.5.2/8.5.3(S), section 6.1.8 still identifies "supplier performance issues" as a source of evaluation; you have proposed the modification of SOP 8.4 (M) "Analysis of Quality Metrics" to perform monthly trend analyses and clarify actions steps when a trend is identified relating to a supplier. However, you have not provided documentation or evidence of the proposed correction.
b. You proposed and implemented changes and additions to documentation including the addition of a "Supplier Evaluation Form," modification of SOP 8.4(M), "Analysis of Quality Metrics" to separate service requests from complaints and perform monthly trend analysis, and modify SOP 7.2.3(M), "Complaint Handling" to separate service request categories from complaint categories. As a preventive action, you have established a Quality Review Board to review all quality indicators, including complaints, nonconforming material reports, trends, etc. However, you have not provided documentation or evidence of the proposed correction.
c. Responses pertaining to part c) are contained within part b).
3. Failure to establish and maintain adequate procedures for complaint handling to include review, evaluation, and investigation of any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications, as required by 21 CFR 820.198(c). For example, 6 out of 40 complaints reviewed during the inspection were not adequately investigated. Specifically:
a. Complaint 10818, dated 9/10/09, reported a patient that had received a 2nd degree bum from a Blanketrol III device, and was classified as a Category Three. Complaint Handling procedure SOP 7.2.3(M) Rev. 13, section 188.8.131.52 states "It is CSZ policy to retrieve alleged failed product to ensure adequate root cause determination and corrective action." No fundamental cause for the device malfunction was reached.
b. Complaint 10637, dated 8/18/09, reported that a Blanketrol II device cooled past its setpoint when in automatic mode. The unit was set to 33°C and cooled to 30°C, and did not return to 33°C as expected. The unit maintained operation at 30°C. The complaint investigation did not include any evidence of the testing of the alleged defective unit, and you were unable to locate the RMA documentation that would support activities performed in an investigation.
c. Complaint 10668, dated 8/19/09, reported two complaints ofbums from the same device. Complaint Handling procedure SOP 7.2.3(M) Rev. 13, section 184.108.40.206 states "If product is not returned within 30 days (90 days for international return) and after three attempts, the customer will be notified of such... Document the three attempts ..." You provided evidence the one attempt was made, and that a second attempt was discussed with no evidence of its completion within 90 days of having received the complaint.
d. Complaint 08836, dated 5/4/09, reported debris contained within a seal for a pouch of a sterile 11" by 12" pad. The debris in the seal was confirmed, but the cause of the debris was not investigated. You admitted that an investigation should have been performed for this complaint and was not.
e. Complaint 11020, dated 10/13/09, reported a Blanketrol 233 device had no display with the power switch on and that fuses had blown twice. Complaint Handling procedure, SOP 7.2.3 Rev. 13, section 220.127.116.11 states "If product is not returned within 30 days (90 days for international return) and after three attempts, the customer will be notified of such and advised that if the product is not received within 10 days (30 days for international return) the complaint will be closed and (if applicable) credit may not be given. Document the three attempts ..." No evidence was provided that suggests the devices were asked to be returned for investigation and no investigation has otherwise been conducted.
f. Complaint Handling procedure, SOP 7.2.3 Rev. 13, section 3.1 "Definitions: Complaint" defines a complaint as "Any written, electronic or oral communication that alleges deficiencies related to the identity, quality, durability, safety or performance of a medical device that has been released for distribution." In addition, SOP 7.2.3 Rev. 13, section 18.104.22.168 states that sources of complaints can include "returned goods form (RMA)." Return Material Authorization (RMA) 7526 states "CUSTOMER STATES THAT NEW BD HAS AN A/D ERROR RETRIED OLD BD -NO ERROR OF THIS TYPE CAT ONE-REPLACEMENT." No complaint was opened for this RMA.
We have reviewed your responses and have concluded that the adequacy cannot be determined. You opened a CAPA to address the identified complaint deficiencies. You have been in contact with the complainants for 10818, 10668, and 11020 to obtain further information. You have contacted the complainant for 10637 and are awaiting their testing results. Complaint 08836 was concluded with the opening of a CAPA, identification of the root cause of the debris in seals, and approval of the corrective action. Complaint Handling procedure, SOP 7.2.3 Rev. 16 was provided in your response and has altered the need to perform investigations to include all complaints. You created a Complaint Review Project Plan to perform a retrospective complaint review back to June 2009. However, documented evidence per Complaint Handling procedure, SOP 7.2.3 Rev. 13, section 22.214.171.124 was not provided for any of the proposed complaint investigations beyond the summary in your response. Additionally, preventive actions were proposed but the effectiveness of the actions has not been determined.
4. Failure to establish and maintain adequate procedures for validating the device design, including software, to ensure that devices conform to user needs and intended uses and include testing of production units under actual or simulated use conditions, as required by 21 CFR 820.30(g). For example, the software used in the microprocessor boards on the Blanketrol II device does not have a software validation protocol established and the software has not been validated. You were unable to determine how many software revisions had been released for the Blanketrol II and what changes were made during each revision.
We have reviewed your responses and have concluded that they are inadequate because you have not completed your review and validations for all products that require software validation. You have stated that you have completed a software validation for the current version of the Blanketrol II device, but no documented evidence was provided for our review. You opened a corrective action and identified five other devices requiring software validation in the response dated 2/26/10. The effectiveness ofthe evidence and implementation of the correction, the corrective action, and the proposed preventive action cannot be determined. Additionally, you have not determined the fundamental cause for a systemic failure to validate software, and no corrective action or preventive action to correct the systemic failure has been taken and determined to be effective.
5. Failure to adequately establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met, as required by 21 CFR 820.75(b). For example, your Process Instruction P-001, Rev. O describes that, for the Cold Therapy Packaging Process, three empty pouches should be inspected per visual standard GT-509, and that every twenty-fifth pouch should be sealed empty and held for inspection. However, the investigator noticed during the inspection that your operator did not use visual standard GT-509 to perform inspections. In addition, the investigator did not witness the segregation or inspection of every twenty-fifth pouch, and no documented evidence including Form 0156 could support the inspection of every twenty-fifth pouch per Process Instruction P-001 and Quality Instructions for Cold Therapy/ Heat Therapy Pads Q-001, Rev. W.
We have reviewed your responses and have concluded that the adequacy cannot be determined. You have not provided documented evidence including a description and evidence of implementation of the correction, the corrective action, and the proposed preventive action. Your proposed correction was to modify documents referred to as the P-Sheet (Production Instruction document) and the Q-Sheet (Quality Instruction document) to be in alignment with FDA expectations, which was not complete as of 2/26/10 and is the main violation of this observation. You also opened a CAPA to conduct a review of all manufacturing operations to ensure operators are trained on procedures being implemented and review to ensure the procedures appropriately monitor and control process parameters. Additional training that covers 21 CFR 820 was provided. However, no documented evidence and implementation of the correction, the corrective action, and the proposed preventive action was provided for our review.
6. Failure to adequately ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use, as required by 21 CFR 820.70(g). For example, no installation qualification had been performed on the heat bar sealer used to seal sterile devices, following receipt at your facility.
We have reviewed your responses and have concluded that the adequacy cannot be determined. You did not provide documented evidence of correction for our review. Specifically, you purchased a new Bar Sealer on 11/20/2009, and completed its validation on 12/23/2009. However, evidence of installation qualification was not provided. You opened and subsequently closed a CAPA to investigate the sterile packaging seal integrity failures, but no documented evidence and implementation of the correction, the corrective action, and the proposed preventive action was provided for our review.
Our inspection also revealed that your Blanketrol series Hyper/Hypothermia System devices and your Extra Corporeal Membrane Oxygenation Blood Temperature Control System are misbranded under section 502(t)(2) of the Act, 21 U.S.C. 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. 360i, and 21 CFR Part 803 - Medical Device Reporting (MDR) regulation. Significant deviations include, but are not limited to, the following:
7. Failure to report to the FDA no later than 30 calendar days after the day that you receive or otherwise become aware of information, from any source, that reasonably suggests that a device that you market may have caused or contributed to a death or serious injury, as required by 21 CFR 803.50(a)(1). For example:
a. Complaint 10818, dated September 10, 2009 indicates that a patient received a second degree burn that is described as "frostbite like" from the Blanketrol series Hyper/Hypothermia System. The patient lost skin. The hospital staff intervened with a spray debridement. Complaint 10818 meets the definition of a serious injury and it was not reported within 30 calendar days after the day that you received or otherwise became aware of the information.
b. Complaint 10676, dated August 19, 2009, indicates that a patient was infected with Cupravidus Pauculus and that you had a similar type of event the previous year. The infection is associated with the Extra Corporeal Membrane Oxygenation Blood Temperature Control System. Complaint 10676 meets the definition of a serious injury and it was not reported within 30 calendar days after the day that you received or otherwise became aware of the information.
8. Failure to develop, maintain, and implement written MDR procedures for internal systems that provide for a timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements, as required by 803.17(a)(1). For example: for complaints 10818 and 10676, you justified not reporting to the FDA these complaints because of user error. However, your MDR Procedure states that if user error causes or contributes to a death or serious injury, it meets the definition of an MDR reportable event. Your definition of cause or contribute is consistent with the 21 CFR 803 Regulation and therefore it demonstrates that you failed to implement your MDR procedure.
We have reviewed your responses dated January 27, 2010, February 26, 2010 and April 9, 2010 to your FDA 483 pertaining to Medical Device Reporting. Also, we reviewed your updates to the Customer Relationship Manager database which documents and manages complaint related information; and the Medical Device Reporting Procedure, SOP 8.5.2(M), that states the requirement to complete the "MDR Decision" form for all CAT Two and CAT Three complaints. As written, your definitions of a CAT Two and CAT Three only include situations where the device failure or patient injury occurs when patient therapy is interrupted. You must consider all situations where the device was or may have been attributed to, or a factor in a reportable adverse event, regardless of whether or not the event describes an interruption in therapy.
Your definitions for CAT Two and CAT Three do not capture the full concept of an adverse event that is MDR reportable as defined in CFR 803. Please contact RSMB at RSMB@FDA.HHS.GOV, for advice on how to correct your MDR procedural deficiencies.
Please note, your January 27, 2010 response states the following for complaint 10818:
"CSZ believes there is no potential for harm to other patients associated with this incident since the failure was due to human error."
The potential for harm to other patients exists if end users do not realize the characteristics of the device. If the event occurs again it must be investigated and reported as appropriate. A device-related death or serious injury caused by user error is MDR reportable. Please be aware that for each MDR reportable event, one MDR report must be submitted for each type of event, for each patient, for each medical device involved.
Our inspection also revealed that the Blanketrol II Model 222R, Blanketrol III (Model 233) and CoolBlue Systems; the Norm-O-Temp devices; the WarmAir 135 devices; and Blanketrol II and Hemotherm devices modified to an upper operating temperature of 48°C are adulterated under section 501 (f)(1)(B) of the Act, 21 U.S.C. 351(f)(1)(B), because you do not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. 360(a), or an approved application for an investigational device exemption (IDE) under section 520(g) of the Act, 21 U.S.C.360(g). The device is also misbranded under section 502(0) the Act, 21 U.S.C. 352(0), because you did not notify the agency of your intent to introduce the device into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. 360(k). For a device requiring premarket approval, the notification required by section 510(k) of the Act, 21 U.S.C. 360(k), is deemed satisfied when a PMA is pending before the agency, 21 CFR 807.81(b). The kind of information you need to submit in order to obtain approval or clearance for your device is described on the Internet at http://www.fda.gov/cdrh/devadvice/3122.html. The FDA will evaluate the information you submit and decide whether your product may be legally marketed.
You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.
We are requesting that you submit to this office on the schedule below, certification by an outside expert consultant that he/she has conducted an audit of your establishment's manufacturing and quality assurance systems relative to the requirements of the device QS regulation (21 CFR, Part 820). You should also submit a copy of the consultant's report, and certification by your establishment's Chief Executive Officer (if other than yourself) that he or she has reviewed the consultant's report and that your establishment has initiated or completed all corrections called for in the report. The initial certifications of audit and corrections and subsequent certifications of updated audits and corrections should be submitted to this office by the following dates:
• Initial certifications by consultant and establishment - December 15, 2010.
• Subsequent certifications - March 15, 2011, and June 15, 2011.
Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
Your response should be sent to: Mark E. Parmon, Compliance Officer, U.S. Food and Drug Administration, 6751 Steger Drive, Cincinnati, Ohio 45237. If you have any questions about the content of this letter please contact: Compliance Officer Parmon at (513) 679-2700 ext. 162 or Inark.firstname.lastname@example.org.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your firm's manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.
Teresa C. Thompson